Novel Diagnostics and Therapeutics in Dry Eye Disease

Advances in Ophthalmology and Optometry 1 (2016) 1–20

ADVANCES IN OPHTHALMOLOGY AND OPTOMETRY

Novel Diagnostics and Therapeutics in Dry Eye Disease Daniel Sarezky, MD, Mina Massaro-Giordano, MD, Vatinee Y. Bunya, MD* Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, 51 North 39th Street, Philadelphia, PA 19104, USA

Keywords 

Meibomian gland dysfunction  Tear osmolarity  Interferometry In vivo confocal microscopy  Fluorophotometry  Intense pulsed light  Scleral lens  Amniotic membrane 

Key points 

Dry eye disease affects millions, with a substantial quality of life and economic burden.



There has been an enormous increase in research into new diagnostics and therapeutics for dry eye disease, particularly over the last 5 years.



For diagnostics, there are a variety of new imaging techniques that are available such as meibography, interferometry, and confocal microscopy that show promise in the evaluation of dry eye patients. While initial research on the TearLab system for measuring tear osmolarity showed promising results, more recent evidence suggests high variability and unclear clinical utility.



For therapeutics, there are several novel eyelid treatments now available including intense pulsed light (IPL), Lipiflow, and meibomian gland probing.



Scleral lenses and amniotic membranes are helpful in managing patients with severe ocular surface disease.



Recent work on multiple new technologies shows that considerable advances have been made in the diagnosis and treatment of this disease, providing hope that its burden will greatly decrease in future years.

Disclosure: M. Massaro-Giordano receives funding support from Research to Prevent Blindness. V.Y. Bunya has received research supplies from TearLab for a separate study and receives support from the National Eye Institute (K12-EY-015398) and Research to Prevent Blindness. D. Sarezky has nothing to disclose.

*Corresponding author. E-mail address: [email protected] 2452-1760/16/$ – see front matter http://dx.doi.org/10.1016/j.yaoo.2016.03.016

Ó 2016 Elsevier Inc. All rights reserved.

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INTRODUCTION Estimates of the prevalence of dry eye are between 5% and greater than 30% of adults [1]. Two large epidemiologic studies, the Women’s Health Study and the Physicians’ Health Study, estimated that 3.23 million women and 1.68 million men aged 50 years and older have dry eye symptoms [2,3]. Because of the aging population, and because dry eye disproportionately affects the elderly, its prevalence is predicted to double in the coming decades [3]. The burden of dry eye is significant, with effects on visual function, activities of daily living, professional work, and quality of life [1]. Dry eye is also associated with substantial economic costs, including direct costs from doctors’ visits, medications, and procedures, as well as indirect costs from decreased productivity, reduced quality of life, and general impairment in functioning [4]. A recent economic analysis estimated that the average annual cost of managing an American patient with dry eye was $783, which, when adjusted for the prevalence of dry eye, amounted to $3.84 billion across the US health care system [5]. Traditional mainstays of dry eye treatment have included over-the-counter artificial tears, warm compresses, and lid hygiene with baby shampoo [6], a practice that was first recommended in a case report with Selsun ointment in 1954 [7]. Over the last decade, there has been a rapid increase in the available diagnostic and treatment modalities for dry eye disease. This article reviews recent developments regarding many of these new technologies. DIAGNOSTICS Tear Osmolarity Tear osmolarity has been recognized for decades as a potential quantitative measure for dry eye [8]. There are 2 primary methods used for the measurement of tear osmolarity: freezing point depression and electrical impedance [9]. The TearLab Osmolarity System (TearLab Corp, San Diego, CA) was approved in 2009 for use and greatly facilitated in-office testing [10]. The device uses a hand-held pen to collect a small sample of tears (50 nL) and then yields a quantified measurement of tear osmolarity in less than a minute [11]. Initial studies showed promise for the device’s diagnostic utility. A multicenter study of 314 patients showed that osmolarity measured by the TearLab system had better correlation with a calculated dry eye severity score than other assessments, including Schirmer testing, corneal staining, and the Ocular Surface Disease Index (OSDI) questionnaire [12]. A different analysis of the same data showed tear osmolarity to have high specificity (92%) and sensitivity (73%) compared with the severity score [13]. These authors found less variability in osmolarity over a 3-month period than corneal and conjunctival staining and meibomian gland grading. They then started the patients with the most severe signs and symptoms on cyclosporine and found that their tear osmolarities showed a significant decline after a second 3-month period, although none of the other dry eye indices showed any significant improvement [12]. Note that several of the investigators of these 3 studies have financial interests in

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the TearLab Corp. Other groups also found significant correlations between tear osmolarity and other indices of dry eye severity [14,15]. However, other recent studies have called into question the reliability and clinical utility of the TearLab system. Bunya and colleagues [16] and Fuerst et al [17] failed to show significant correlations between tear osmolarity and dry eye symptoms and signs. Other studies have reported similar Messmer and colleagues [18] or even higher osmolarity in normal subjects compared to those with dry eye disease Szalai et al [19]. Amparo and colleagues [10] retrospectively reviewed charts of 186 patients with osmolarity data from the TearLab system. Although symptoms as measured by the OSDI correlated with corneal fluorescein staining, there was no correlation between change in tear osmolarity and symptoms. The investigators concluded that it was unclear whether tear osmolarity as measured by the TearLab system was useful for following patients with dry eye over time. Additional concerns have been raised regarding the variability of measurements using the TearLab system. Khanal and Millar [20] found variations of as much as 35 mOsm/L in consecutive tear osmolarity measurements in patients without dry eye. Bunya and colleagues [21] took 3 consecutive osmolarity measurements in 74 eyes, finding the measurements to be highly variable in both patients with dry eye and patients without dry eye. Therefore, despite its speed and ease of use, the TearLab system should be used cautiously in the clinical setting because recent literature has shown an inconsistent ability to differentiate patients with dry eye from those without, questionable utility in following patients with dry eye over time, and high variability among measurements. Further studies are needed to elucidate its clinical utility. Oculus Keratograph The Oculus Keratograph (Oculus, Wetzlar, Germany) is a corneal topographer with multiple features that analyze the ocular surface, including tear meniscus height (TMH), noninvasive keratograph break-up time (NIKBUT), meibography, and conjunctival hyperemia assessment (Fig. 1). Although there have been recent studies evaluating both the Oculus Keratograph 4 and the newer 5M model, only those evaluating the Oculus Keratograph 5M are considered in this article. Several recent studies have evaluated individual keratograph modalities with generally promising results. Hong and colleagues [22] measured NIKBUT in 85 patients, finding it to be significantly decreased in patients with dry eye compared with controls. There also was a good correlation with other dry eye measurements, including Schirmer testing. Koh and colleagues [23] evaluated TMH in 46 patients, finding that it was significantly lower in patients with dry eye compared with controls, although this measure was artificially increased if taken after the NIKBUT measurement (and forced eyelid opening). Baek and colleagues [24] also evaluated TMH in 64 eyes and found it to correlate well with Optical Coherence Tomography (OCT). Schirmer test, tear break-up time (TBUT), and corneal staining score.

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Fig. 1. Oculus Keratograph 5M. (Top) Keratograph unit. (Middle) Noninvasive keratograph break-up time. (Bottom) Meibography. (Courtesy of Oculus, Wetzlar, Germany; with permission.)

Ngo and colleagues [25] subjectively graded meibomian gland dropout from meibography images obtained with the Oculus Keratograph 5M in 40 subjects, finding both interobserver and intraobserver reproducibility measures to be highly correlated. In 128 patients, Finis and colleagues [26] used the meibography function to assess meibomian gland atrophy. Compared with a standardized device to measure meibomian gland blockage, meibomian gland atrophy as measured by the keratograph was significantly correlated with the lack of

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expressibility of meibomian glands. Meibography was also correlated with keratograph TBUT and the age of the patient. Wu and colleagues [27] used the keratograph in 30 eyes to assess bulbar redness versus 3 image-based subjectively graded scales. All subjective scales were significantly correlated with the keratograph, with the objective keratograph having the highest reproducibility. However, a recent large study questioned the utility of some of the keratograph functions. Abdelfattah and colleagues [28] evaluated NIKBUT, TMH, and meibography modes in the keratograph in 296 eyes. TMH was significantly higher in the dry eye group than in the control group, even though traditional fluorescein TMH was higher in the control group. The investigators speculated that perhaps infrared reflectance from the conjunctiva artificially increased the measured TMH. In addition, the NIKBUT was not statistically different between the dry eye and control groups, whereas fluorescein TBUT was significantly shorter in the dry eye group. They did find a higher percentage of meibomian gland atrophy in the dry eye group, as expected. Therefore, although the Oculus Keratograph 5M provides detailed images and measurements, its clinical utility remains uncertain. Minimal study has been done to coordinate the keratograph’s findings to ocular symptoms. Future, larger studies are needed to determine the diagnostic value of the keratograph for the evaluation of dry eye disease. Interferometry Interference, which occurs when 2 beams of light arrive at the same region of space along different paths, can occur either constructively or destructively. In nature, interference of white light results in the changing colors observed in a soap bubble or a thin film of oil floating on water. When monochromic light is used, a series of light and dark bands called interference fringes are observed. In the case of the ocular surface, the pattern of these fringes provides information about the thickness and topography of the tear film [29]. Several interferometers have been used to evaluate the ocular surface in patients with dry eye disease. One such interferometer, the LipiView (TearScience Inc, Morrisville, NC), is commercially available (Fig. 2). Blackie and colleagues [30] used a prototype to the LipiView (the Kolis interferometer) to evaluate 137 consecutive patients presenting for routine care. They found a significant correlation between symptoms and decreased lipid layer thickness. Eom and colleagues [31] used the LipiView to study 30 eyes with meibomian gland dysfunction (MGD) and 25 normal eyes. They found that the lipid layer thickness was significantly thinner in the dry eye group than in controls, and that this was correlated with meibomian gland loss on meibography. In a larger study, Finis and colleagues [32] evaluated the LipiView interferometer in 199 eyes, finding a significant correlation between lipid layer thickness and the number of expressible meibomian glands. There was also a statistically insignificant trend of increasing symptoms with decreased lipid layer thickness.

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Fig. 2. LipiView. (Courtesy of TearScience Inc, Morrisville, NC; with permission.)

Hosaka and colleagues [33] used a different device, the Quore interferometer, in 28 patients with dry eye and 14 control patients to evaluate central thickness of the precorneal tear film. The tear film was significantly thinner in patients with dry eye and was correlated with other dry eye indices. Punctal occlusion resulted in improvement of tear film thickness, as well as TMH, fluorescein scoring, TBUT, and Schirmer testing. Hwang and colleagues [34] also evaluated lipid layer thickness of the tear film but instead used a novel interferometer created by the investigators to show that the lipid layer thickness was significantly thinner in patients with dry eye syndrome than in controls. Taken together, these studies indicate that interferometry measurements have strong associations with signs and symptoms of dry eye, and thus may have a significant role in dry eye diagnosis and assessment of treatment effectiveness in the future. Matrix Metalloproteinase-9 Detection Matrix metalloproteinases, particularly matrix metalloproteinase-9 (MMP-9), have been implicated in the pathophysiology of dry eye. Specifically, evaporation-induced keratitis has been shown to lead to MMP production by the corneal epithelium, thereby leading to disruption of the epithelium, staining, and many of the symptoms associated with dry eye [35]. Chotikavanich and colleagues [36] assayed tear MMP-9 quantitatively in patients with dry eye. Although their method involved multiple steps, including incubation of samples overnight that made it impractical for routine clinical use, they found significant correlations between tear MMP-9 level and the severity of dry eye as measured by subjective OSDI scores, fluorescein staining, and TBUT.

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InflammaDry (InflammaDry; Rapid Pathogen Screening, Inc, Sarasota, FL) is a device designed for in-office use that, with a small sample of tears, gives a qualitative positive or negative result for the presence of MMP-9 in about 10 minutes (Fig. 3) [35]. Sambursky and colleagues performed InflammaDry on 206 patients, including 143 with dry eye and 63 controls. A clinical diagnosis of dry eye was used as their gold standard and was made by meeting certain criteria for all of the following measurements: OSDI, Schirmer, TBUT, and staining. Of the 143 patients who met their clinical criteria for dry eye diagnosis, InflammaDry had an 85% sensitivity and 94% specificity, as well as 97% positive predictive value and 73% negative predictive value, thereby supporting InflammaDry’s utility as a diagnostic test [37]. The same group found similar results in a repeat study published a year later [38]. Of note, an author for both of these studies has an affiliation with the manufacturer of InflammaDry (Rapid Pathogen Screening, Inc.). However, elevations in MMP-9 are not specific for dry eye and can be seen in other ocular conditions such as vernal keratoconjunctivitis [35,39] and peripheral ulcerative keratitis [40]. In addition, it is unclear how well InflammaDry performs in identifying patients with mild dry eye disease [41]. Early research seems to verify InflammaDry’s accuracy in detecting established dry eye disease, although further study is needed to explore its utility in early and mild disease stages. In addition, more study is needed to evaluate InflammaDry across different causes of dry eye. Much of the basic science research on matrix metalloproteinases has involved keratoconjunctivitis sicca, especially in patients with Sjo¨gren syndrome (SS) [35]. Future work focusing on how InflammaDry measurements vary between dry eye patients with and without SS would be of interest. Further studies also should be directed at determining how InflammaDry is affected by treatment. Confocal Microscopy In vivo confocal microscopy (IVCM) allows high-resolution imaging of microscopic structures within tissues, without the need for fixation or staining [42]. It has generated considerable research in various ocular surface diseases, including dry eye [43]. Multiple IVCM studies in patients with dry eye have shown decreased epithelial cell density and both abnormal and decreased corneal nerves [44–46]. These changes have been shown in studies across different dry eye causes, including SS [47] and chronic ocular graft-versushost disease (GVHD) [46]. Although not typically associated with neurotrophic keratopathy, one study correlated the decrease in subbasal corneal nerves with

Fig. 3. InflammaDry. (Courtesy of InflammaDry, Rapid Pathogen Screening, Inc., Sarasota, FL.)

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decreased corneal sensitivity on esthesiometry in patients with dry eye. This study also showed that not only were corneal nerves decreased in number, but they also showed increased tortuosity and beading [48]. A recent study by Kheirkhah and colleagues [49] investigated corneal nerves in patients with dry eye and response to treatment. They randomized 60 patients with MGD to receive either artificial tears, loteprednol 0.5% drops, or loteprednol 0.5%/tobramycin 0.3% drops. They subdivided each group into subjects with near-normal and low corneal subbasal nerve fiber lengths at baseline. They found an improvement in symptoms only in patients with nearnormal baseline nerve lengths treated with either artificial tears or loteprednol alone, concluding that patients with severely damaged corneal nerves may not detect improvement in the ocular surface, thereby resulting in a decreased response to treatment. IVCM studies in patients with MGD also have shown changes in the eyelids. For example, Ibrahim and colleagues [50] used confocal microscopy to evaluate meibomian glands in both patients with MGD diagnosed clinically and controls. The meibomian gland acinar units were less dense and on average larger in the patients with MGD, and also an increase in periglandular inflammatory cells occurred. These parameters were significantly correlated with TBUT, corneal staining, and clinical evaluation of meibomian gland expressibility and dropout. When a clinical diagnosis of MGD was used as the gold standard, all confocal parameters had sensitivities and specificities of at least 80%. A more recent study by the same investigators compared patients with atopic keratoconjunctivitis (AKC) with those with MGD and controls. Meibomian gland fibrosis and atrophy in the AKC patients were significantly worse than in the MGD and control groups, which was hypothesized to be caused by the effects of inflammation in AKC [51]. IVCM has also been used in dry eye disease to visualize ocular surface inflammation directly. Kheirkhah and colleagues [52] found significantly higher dendritic cell size and density in the corneas of patients with dry eye. These parameters were even greater in patients with aqueous-deficient dry eye related to an underlying systemic immune condition such as SS and GVHD. Wakamatsu and colleagues [53] evaluated inflammatory cell densities and found these to be increased in patients with dry eye with SS compared to patients with dry eye without SS, as well as being greater in both of these dry eye groups than in controls. They also found conjunctival epithelial cell density to be lower in patients with dry eye than in controls. There is some evidence that the location of the immune cells may predict a response to treatment. Qazi and colleagues [54] compared a subset of 5 patients with MGD refractory to treatment to several groups of controls, including those with dry eye who responded to treatment. In the subset of nonresponders, using IVCM, they found increased immune cells specifically in the palpebral conjunctiva, although not in the cornea. A recent study using IVCM found that corneal endothelial cell density was significantly lower in a cohort of moderate to severe dry eye disease versus

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controls. The investigators also found significant correlations between the endothelial cell densities and other measures of dry eye severity, including OSDI scores and corneal fluorescein staining. The investigators postulated that the loss of endothelial cells could be the result of concomitant loss of corneal nerves or the presence of dry eye–associated inflammation [55]. In addition, Randon and colleagues [56] used IVCM to evaluate for demodex infection in patients with dry eye, finding comparable detection with traditional light microscopy of depilated eyelashes. In their subset of 18 patients with dry eye with anterior blepharitis, all were found to have demodex infection. IVCM has yielded productive research into the morphologic changes of the ocular surface and the eyelids in dry eye disease. Further work should be directed at translating these changes into novel therapeutic strategies. Fluorophotometry Fluorophotometry is the measurement of light given off by a fluorescent substance. In dry eye research, the clearance of fluorescein from the ocular surface, whether measured by imaging the cornea to evaluate epithelial permeability or directly via tear samples, has been studied. Go¨bbels and colleagues [57] randomized 40 patients with dry eye to receive either benzalkonium chloride–containing artificial tears or preservative-free artificial tears 6 to 9 times daily, taking fluorophotometric measurements of the cornea. Preservative-free artificial tears significantly decreased epithelial permeability after 6 weeks of treatment, but the benzalkonium tears led to an increase in epithelial permeability. More recently, Fahim and colleagues [58] used fluorophotometry to evaluate 16 symptomatic patients with dry eye with decreased Schirmer testing and 16 controls. The patients with dry eye had significantly increased corneal fluorescein concentration compared with controls, and this persisted even an hour later. Several other studies have measured fluorescein clearance directly in tear samples, which when delayed has been associated with proinflammatory cytokines and ocular surface inflammation [59]. Alfonso and colleagues [59] compared fluorophotometry 15 minutes after instillation of fluorescein in 40 patients presenting with ocular irritation with 40 asymptomatic controls. The fluorescein concentration at 15 minutes was higher in the ocular irritation group, showing a significant correlation with symptoms. Reduced fluorescein clearance showed a higher positive predictive value for irritation than Schirmer testing. Fluorescein concentration also was correlated with decreased corneal and conjunctival sensation measured by an esthesiometer. Macri and colleagues [60] found a similar correlation between fluorescein clearance from tear samples and symptoms, as well as corneal fluorescein staining, Schirmer testing, and meibomian gland evaluation. In addition, Garcia and colleagues [61] evaluated fluorescein clearance from tear samples in 24 young, healthy adults. Fluorescein concentration 15 minutes later was significantly higher in the evening than at midday, indicating that decreased tear turnover may happen over the course of the day.

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However, studies to date of fluorophotometry are limited by small sample size and by the use of multiple approaches and devices. In addition, fluorophotometry is impractical for routine clinical use, because it requires multiple, serial measurements after fluorescein administration [57,58] and an involved laboratory analysis [59–61]. THERAPEUTICS Intense Pulsed Light Intense pulsed light (IPL) involves targeting pigmented or vascular lesions with visible and infrared light. On absorption by targeted structures, the light turns into heat, thereby destroying the lesions. It has been used extensively in dermatology, including for port-wine stains, venous malformations, and telangiectasias [62,63]. IPL as a treatment of MGD is credited to Rolando Toyos, MD, who in 2002 noted improvement in dry eye symptoms in patients who underwent this treatment of facial rosacea [64,65]. The proposed mechanism is that IPL treatment causes regression of telangiectasias surrounding meibomian glands in MGD, thereby reducing inflammatory mediators and bacterial overgrowth and leading to reduction of symptoms. In addition, IPL may melt abnormal, viscous meibum, thereby improving flow through the meibomian glands. Toyos and colleagues [65] published a retrospective review of 91 patients presenting with dry eye symptoms who were treated with IPL. They found that 93% of patients had improvement in symptoms and 87% in TBUT over a median of 4 follow-up visits. Thirteen percent of patients reported adverse events, mostly related to localized redness and swelling, but there were no significant adverse events. Vora and colleagues [64] studied 37 patients retrospectively, all with at least 3 IPL treatments. They found significant improvements in clinical signs and in OSDI assessments, although some patients required additional treatment after 6 to 12 months. Craig and colleagues [62] described 28 patients with mild to moderate MGD, all having IPL in one eye and placebo treatment to the other (a blocking filter was applied to the tip of the IPL probe, and the researcher was masked to the eye receiving the treatment). Comparing the 2 eyes, they found a significant improvement in the lipid layer graded by interferometry, TBUT, and symptoms in the treated eye compared with the control eye. Overall, 86% of patients noted reduced symptoms in the treated eye by 45 days. IPL is currently US Food and Drug Administration approved for the treatment of dermatologic disease, including for telangiectasias [63]. There is promising, but limited, mostly retrospective data for the off-label ocular use of IPL that suggest that it may be effective in the management of MGD and ocular rosacea. However, there are several limitations of IPL treatments, including that it cannot be used in darkly pigmented skin, only the lower eyelids are able to be treated because of risk of intraocular absorption with upper lid treatment, and local side effects [64,65]. Larger, randomized controlled studies are needed to determine the clinical role of this technology.

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LipiFlow Although warm compresses remain one of the mainstays of dry eye management, their use is often intensive and ineffective, and better treatments for MGD are needed [66]. LipiFlow (TearScience, Morrisville, NC) is a device intended for in-office treatment of MGD (Fig. 4). It simultaneously provides heat over the palpebral conjunctiva of the upper and lower eyelids, while providing pulsatile external pressure, with the intention of expressing meibomian glands during heating. Initial studies with LipiFlow have shown promising results for the treatment of MGD. Lane and colleagues [66] randomized 139 subjects to a single 12-minute treatment with LipiFlow versus warm compresses daily for 2 weeks. After 2 weeks, the LipiFlow subjects had significant improvement in meibomian gland secretions, TBUT, and symptoms. A crossover design was used in which the original warm compress group was then treated with LipiFlow, and they achieved similar improvement to the original LipiFlow group. There were no differences in adverse events between the two groups. However, a comparison group of patients using warm compresses alone may not be ideal, because this technique lacks lid massage, which likely is important for improving flow through the meibomian glands. Finis and colleagues [67] compared twice-daily warm compresses and massage with a single LipiFlow treatment in a randomized study of 31 patients over 3 months, finding a significant reduction in OSDI scores in the LipiFlow group. Six months later, subjective symptoms remained decreased, as was lipid layer thickness and number of expressible glands as assessed by the Oculus Keratograph 5M [68]. As with the previous studies described, the investigators noted that it was impossible to mask the patients who had treatment, thereby possibly creating a source of bias. In addition, Greiner [69] performed a single treatment with LipiFlow in 42 eyes with MGD, finding improvements in TBUT, OSDI scores, and meibomian gland secretion scores that were maintained 9 months later. At 3 years

Fig. 4. LipiFlow. (Courtesy of TearScience, Morrisville, NC; with permission.)

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of follow-up, the meibomian gland secretion score improvement persisted, although TBUT and OSDI scores returned to baseline [70]. Preliminary studies suggest that LipiFlow is an effective modality for MGD, with the encouraging results that single treatments may have lasting benefits for months beyond the initial treatment. However, patients were not masked to treatment and, therefore, may have been biased to report improvement in symptoms. Future large, double-masked, randomized, clinical trials would be helpful in determining the effectiveness of this treatment. Meibomian Gland Probing In 2010, Maskin [71] reported a novel probing technique for treating MGD. Using viscous topical anesthetic in 25 patients with MGD and lid tenderness, he inserted a beveled, 2-mm solid stainless steel probe into meibomian gland orifices. All but 1 patient had immediate relief in tenderness, and all had persistent relief 4 weeks later. Repeat treatments were only required in 5 of the patients with an average follow-up of almost a year [71]. In a small cohort, Wladis [72] used a similar technique in 40 eyelids of 10 patients with MGD and ocular rosacea, except he used anesthesia with 2% lidocaine with epinephrine 1:100,000. The subjects had significantly improved OSDI scores at 1 and 6 months. Nine of the 10 were able to discontinue doxycycline, and all reported decreased artificial tear use [72]. In addition, another recent small study reported improvements in meibum lipid levels and decrease in meibum viscosity after probing at 1 month following treatment. This study used topical anesthesia with 8% lidocaine with a petroleum base [73]. Based on these preliminary studies, meibomian gland probing is promising as an inexpensive, in-office procedure to treat MGD. However, lack of consensus in type of anesthesia among the 3 studies reviewed questions the degree of patient discomfort involved in this procedure. Further study with larger sample sizes is needed, especially with attention to patient experience during this procedure and duration of effect. MiBoFlo Thermoflo The MiBoFlo Thermoflo system (Mibo Medical Group, Dallas, TX) is a novel device for the treatment of MGD. Per the manufacturer’s website, it uses a heat probe to deliver an effective temperature of 42.2 C (108 F) to a closed eyelid, with the goal of liquefying inspissated secretions to improve meibomian gland function. The manufacturer recommends 3 treatments, 2 weeks apart, reporting a 70% effectiveness rate [74]. To date there have not been any published studies regarding this new technology. BlephEx BlephEx (BlephEx, LLC, Lake Worth, FL) is an in-office tool with a spinning, microsponge tip intended for use along the eyelids and lashes to remove debris in blepharitis (Fig. 5). The product’s website advertises that the procedure lasts 6 to 8 minutes, it may need to be repeated at intervals of 4 to 6 months, and

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Fig. 5. BlephEx. (Courtesy of BlephEx, LLC., Lake Worth, FL; with permission.)

also helps to remove Demodex by eliminating the biofilm generated by eyelid bacteria [75]. To date, there have yet to be any independent, formal studies evaluating the effectiveness of BlephEx. Scleral Lens Scleral lenses are typically rigid, gas-permeable lenses that initially were used clinically for the management of corneal ectasias, but more recently have been studied in advanced ocular surface disease, especially related to chronic GVHD and Stevens-Johnson syndrome. These lenses rest on the sclera and vault over the cornea with a fluid-filled reservoir. They require in-office evaluation and fitting, and there are multiple commercially available types of lenses [76]. The most studied scleral lens in ocular surface disease is the BostonSight PROSE (Prosthetic Replacement of the Ocular Surface Ecosystem) lens (Boston Foundation for Sight, Needham, MA) (Fig. 6). An early retrospective review of 49 consecutive patients (76 eyes) with ocular surface disease treated with this lens found a 92% improvement in quality of life as a result of

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Fig. 6. BostonSight PROSE. (Top left) PROSE lens vaulting over the cornea. (Bottom left) PROSE lens in an eye. (Right) PROSE lens on an applicator prior to insertion. (Courtesy of Boston Foundation for Sight, Needham, MA; with permission.)

reduction in photophobia and pain. Fifty-three percent of patients in this study achieved 2 or more Snellen lines of improvement in visual acuity [77]. Other, more recent retrospective reviews have found similar improvements in symptoms [78–80]. Another retrospective review compared PROSE fitting in patients younger and older than 60 years. They found no difference in fitting time and duration of daily wear with age. However, for all patients with ocular surface disease, the average number of scleral lenses tried was 5.8, the average number of visits was 11.8, and it took on average 196.9 days to complete the fitting process. Although these averages are higher than reported in other studies, the fitting process for scleral lenses is significant, thereby limiting their use in mild to moderate dry eye [76]. Schornack and colleagues [81] evaluated 115 patients with ocular surface disease at a single institution successfully fitted with a Jupiter scleral lens (Visionary Optics, Front Royal, VA), a cheaper option compared with the PROSE lens. Another 20 patients initiated the fitting process, but were unsuccessful. The fitting process took an average of 1.4 lenses per eye and was completed in an average of 3 visits. They found a significant improvement in visual acuity in patients who were successfully fitted. There were no major complications preventing long-term wear of the lenses. Miniscleral lenses have a smaller diameter and thus a smaller fluid reservoir, but have the advantage of being significantly less expensive and simpler to fit

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than traditional scleral lenses. A small study of 7 patients with ocular surface disease fitted with the Blanchard miniscleral lens (Blanchard Contact Lens Inc, Manchester, Canada) found that 4 of the patients were satisfied with their lenses based on decreased discomfort and improved visual acuity [82]. Retrospective data are encouraging that scleral lenses, particularly the PROSE lens, improve patient symptoms and quality of life, and they should be considered in severe cases of dry eye disease. However, their use is limited by cost and fitting difficulty, so miniscleral lenses warrant further study. Amniotic Membrane Amniotic membranes are obtained from human placentas after delivery. Commercially available varieties are either cryopreserved at 80 C, such as the ProKera (Bio-Tissue, Inc, Miami, FL), or they are sterilized and dehydrated. Dehydrated membranes have the benefit of being able to be stored and transported at room temperature, and they do not require an expensive deep freezer [83]. Amniotic membranes have been used for the treatment of various ocular surface disorders, including limbal stem cell deficiency, infectious keratitis, corneal burns, persistent epithelial defects, and conjunctival reconstruction after symblepharon removal. Beneficial effects are attributed not only to epithelial coverage but also to their antiinflammatory properties, which make them a potential therapeutic option for dry eye disease [84]. Cheng and colleagues [85] published a small retrospective review of 10 patients with dry eye disease treated with the ProKera Slim amniotic membrane. The patients achieved a statistically significant decrease in symptoms, use of topical medications, corneal staining, and conjunctival hyperemia. Future, larger studies are needed to determine the utility of amniotic membranes in dry eye. In particular, studies should evaluate the utility of dehydrated amniotic membranes in the treatment of dry eye, such as the AmbioDisk (IOP Ophthalmics, Costa Mesa, CA), because they offer several benefits in terms of convenience and storage compared with cryopreserved membranes. SUMMARY There has been an enormous increase in research into new diagnostics and therapeutics for dry eye disease, particularly over the last 5 years. Although not meant to be comprehensive, the present article examines several of these new technologies. For diagnostic methods, research on the TearLab system for measuring tear osmolarity initially showed promising results, but has more recently suggested high variability and unclear clinical utility. The Oculus Keratograph 5M has multiple modes that can be used to evaluate the ocular surface, although the accuracy of the TMH and noninvasive break-up time measurements has been questioned. Further study is needed to evaluate its clinical utility and also to relate measurements to patient symptoms. Lipid layer thickness and precorneal tear film as measured by the LipiView and other interferometers have

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shown strong associations with signs and symptoms of dry eye. InflammaDry is a device that allows in-office qualitative MMP-9 detection, although MMP-9 levels can be elevated in other ocular conditions and further study is needed to determine its utility in detecting mild dry eye disease. IVCM has yielded research data that have identified many new morphologic features that can be used to evaluate dry eye. Further study designed to translate these findings into therapeutic strategies would be beneficial. In addition, fluorophotometry research is limited by small sample sizes, by the use of multiple approaches and devices, and by lengthy measurement and analysis times, but may hold promise as a diagnostic modality. As for therapeutics, IPL has been used extensively to treat dermatologic disease, but larger studies are needed to determine its role in the treatment of dry eye. Studies of the LipiFlow device for MGD are encouraging, but further studies are needed to determine its effectiveness and duration of effect. Meibomian gland probing is appealing as an inexpensive, in-office procedure, but further work still needs to be done, particularly to address patient comfort and to determine the duration of beneficial effects. MiBoFlo Thermoflo and Blephex are two new devices for treating MGD and blepharitis, but there have yet to be any formal studies published in the literature. Scleral lenses, including the PROSE lens, seem to be an effective treatment reserved for advanced cases of dry eye. In addition, amniotic membranes showed promise in 1 small preliminary study with the ProKera Slim, but larger prospective studies are needed. Dry eye disease affects millions, with a substantial quality of life and economic burden. Recent work on multiple new technologies as detailed in this article shows that considerable advances have been made in the diagnosis and treatment of this disease, providing hope that this burden will greatly decrease in future years. References [1] The epidemiology of dry eye disease: report of the Epidemiology Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf 2007;5(2):93–107. [2] Schaumberg DA, Sullivan DA, Buring JE, et al. Prevalence of dry eye syndrome among US women. Am J Ophthalmol 2003;136(2):318–26. [3] Schaumberg DA, Dana R, Buring JE, et al. Prevalence of dry eye disease among US men: estimates from the Physicians’ Health Studies. Arch Ophthalmol 2009;127(6):763–8. [4] Pflugfelder SC. Prevalence, burden, and pharmacoeconomics of dry eye disease. Am J Manag Care 2008;14(Suppl 3):S102–6. [5] Yu J, Asche CV, Fairchild CJ. The economic burden of dry eye disease in the United States: a decision tree analysis. Cornea 2011;30(4):379–87. [6] Thode AR, Latkany RA. Current and emerging therapeutic strategies for the treatment of meibomian gland dysfunction (MGD). Drugs 2015;75(11):1177–85. [7] Cohen LB. Use of Selsun in blepharitis marginalis. Am J Ophthalmol 1954;38(4):560–2. [8] Tomlinson A, Khanal S, Ramaesh K, et al. Tear film osmolarity: determination of a referent for dry eye diagnosis. Invest Ophthalmol Vis Sci 2006;47(10):4309–15. [9] Tomlinson A, McCann LC, Pearce EI. Comparison of human tear film osmolarity measured by electrical impedance and freezing point depression techniques. Cornea 2010;29(9): 1036–41.

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